Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity

Eriko Koide; Mikaela L Mohardt; Zainab M Doctor; Annan Yang; Mingfeng Hao; Katherine A Donovan; Christina C Kuismi; Alissa J Nelson; Kathryn Abell; Mike Aguiar; Jianwei Che; Matthew P Stokes; Tinghu Zhang; Andrew J Aguirre; Eric S Fischer; Nathanael S Gray; Baishan Jiang; Behnam Nabet

doi:10.1002/cbic.202300141

Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity

Chembiochem. 2023 Oct 4;24(19):e202300141. doi: 10.1002/cbic.202300141. Epub 2023 Jul 24.

Authors

Eriko Koide¹, Mikaela L Mohardt¹, Zainab M Doctor^{1

2}, Annan Yang^{3

4}, Mingfeng Hao¹, Katherine A Donovan^{1

2}, Christina C Kuismi⁵, Alissa J Nelson⁶, Kathryn Abell⁶, Mike Aguiar⁶, Jianwei Che^{1

2}, Matthew P Stokes⁶, Tinghu Zhang⁷, Andrew J Aguirre^{3

4

8}, Eric S Fischer^{1

2}, Nathanael S Gray⁷, Baishan Jiang^{1

2

9}, Behnam Nabet⁵

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
³ Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Human Biology Division Fred, Hutchinson Cancer Center, Seattle, WA 98109, USA.
⁶ Cell Signaling Technology, Danvers, MA 01923, USA.
⁷ Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA 94305, USA.
⁸ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
⁹ Present Address, Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, P. R. China.

PMID: 37088717
PMCID: PMC10590827 (available on 2024-10-04)
DOI: 10.1002/cbic.202300141

Abstract

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small-molecule inhibition or degradation.

Keywords: PROTAC; cancer; degraders; focal adhesion kinase; inhibitors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Focal Adhesion Protein-Tyrosine Kinases / chemistry
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Mice
Neoplasms* / drug therapy
Phosphorylation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Proteolysis Targeting Chimera*
Signal Transduction

Substances

Focal Adhesion Protein-Tyrosine Kinases
Proteolysis Targeting Chimera
Protein Kinase Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding